Research Centre for Molecular Medicine, MTA-DE Lendület Vascular Pathophysiology Research Group, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Debrecen, Hungary.
J Cell Physiol. 2024 May;239(5):e31211. doi: 10.1002/jcp.31211. Epub 2024 Feb 2.
Cataract, a leading cause of blindness, is characterised by lens opacification. Type 2 diabetes is associated with a two- to fivefold higher prevalence of cataracts. The risk of cataract formation increases with the duration of diabetes and the severity of hyperglycaemia. Hydroxyapatite deposition is present in cataractous lenses that could be the consequence of osteogenic differentiation and calcification of lens epithelial cells (LECs). We hypothesised that hyperglycaemia might promote the osteogenic differentiation of human LECs (HuLECs). Osteogenic medium (OM) containing excess phosphate and calcium with normal (1 g/L) or high (4.5 g/L) glucose was used to induce HuLEC calcification. High glucose accelerated and intensified OM-induced calcification of HuLECs, which was accompanied by hyperglycaemia-induced upregulation of the osteogenic markers Runx2, Sox9, alkaline phosphatase and osteocalcin, as well as nuclear translocation of Runx2. High glucose-induced calcification was abolished in Runx2-deficient HuLECs. Additionally, high glucose stabilised the regulatory alpha subunits of hypoxia-inducible factor 1 (HIF-1), triggered nuclear translocation of HIF-1α and increased the expression of HIF-1 target genes. Gene silencing of HIF-1α or HIF-2α attenuated hyperglycaemia-induced calcification of HuLECs, while hypoxia mimetics (desferrioxamine, CoCl) enhanced calcification of HuLECs under normal glucose conditions. Overall, this study suggests that high glucose promotes HuLEC calcification via Runx2 and the activation of the HIF-1 signalling pathway. These findings may provide new insights into the pathogenesis of diabetic cataracts, shedding light on potential factors for intervention to treat this sight-threatening condition.
白内障是导致失明的主要原因，其特征是晶状体混浊。2 型糖尿病患者发生白内障的风险比正常人高 2 至 5 倍。白内障的形成风险随着糖尿病的持续时间和高血糖的严重程度而增加。羟磷灰石沉积存在于白内障晶状体中，可能是晶状体上皮细胞（LEC）成骨分化和钙化的结果。我们假设高血糖可能会促进人晶状体上皮细胞（HuLEC）的成骨分化。含有过量磷酸盐和钙的成骨培养基（OM）与正常（1 g/L）或高（4.5 g/L）葡萄糖一起用于诱导 HuLEC 钙化。高葡萄糖加速并加剧了 OM 诱导的 HuLEC 钙化，同时伴随着高血糖诱导的成骨标志物 Runx2、Sox9、碱性磷酸酶和骨钙素的上调，以及 Runx2 的核转位。在缺乏 Runx2 的 HuLEC 中，高葡萄糖诱导的钙化被消除。此外，高葡萄糖稳定了缺氧诱导因子 1（HIF-1）的调节α亚基，触发 HIF-1α的核转位，并增加了 HIF-1 靶基因的表达。HIF-1α或 HIF-2α 的基因沉默减弱了 HuLEC 的高葡萄糖诱导的钙化，而缺氧模拟物（去铁胺、CoCl）在正常葡萄糖条件下增强了 HuLEC 的钙化。总的来说，这项研究表明，高葡萄糖通过 Runx2 和 HIF-1 信号通路促进 HuLEC 钙化。这些发现可能为糖尿病性白内障的发病机制提供新的见解，并为治疗这种威胁视力的疾病提供潜在的干预因素。
